FI97388C - Förfarande för framställning av heterocykliska NMDA-antagonister - Google Patents
Förfarande för framställning av heterocykliska NMDA-antagonister Download PDFInfo
- Publication number
- FI97388C FI97388C FI912382A FI912382A FI97388C FI 97388 C FI97388 C FI 97388C FI 912382 A FI912382 A FI 912382A FI 912382 A FI912382 A FI 912382A FI 97388 C FI97388 C FI 97388C
- Authority
- FI
- Finland
- Prior art keywords
- piperidine
- carboxylic acid
- alkyl
- ester
- methyl
- Prior art date
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- 239000005557 antagonist Substances 0.000 title claims abstract description 6
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 59
- 238000002360 preparation method Methods 0.000 title claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 title claims 3
- -1 phosphonate ester Chemical class 0.000 claims description 226
- 150000001875 compounds Chemical class 0.000 claims description 143
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 239000001257 hydrogen Substances 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 11
- YEEABICQMLEYCN-UHFFFAOYSA-N 3-(2-phosphonoacetyl)piperidine-2-carboxylic acid Chemical compound OC(=O)C1NCCCC1C(=O)CP(O)(O)=O YEEABICQMLEYCN-UHFFFAOYSA-N 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- YEEABICQMLEYCN-IYSWYEEDSA-N (2r,3s)-3-(2-phosphonoacetyl)piperidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1NCCC[C@@H]1C(=O)CP(O)(O)=O YEEABICQMLEYCN-IYSWYEEDSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000004954 trialkylamino group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
- NCODCYVTBFCISE-UHFFFAOYSA-N piperidine-1-carbonyl piperidine-1-carboxylate Chemical class C1CCCCN1C(=O)OC(=O)N1CCCCC1 NCODCYVTBFCISE-UHFFFAOYSA-N 0.000 claims 1
- 150000003235 pyrrolidines Chemical class 0.000 abstract description 6
- MNQZHTRAKIMKJF-UHFFFAOYSA-N piperidin-3-ylphosphonic acid Chemical class OP(O)(=O)C1CCCNC1 MNQZHTRAKIMKJF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 200
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 112
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 105
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 239000000376 reactant Substances 0.000 description 45
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 44
- 239000002904 solvent Substances 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- 238000010898 silica gel chromatography Methods 0.000 description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 34
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 30
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 23
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 23
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 125000005907 alkyl ester group Chemical group 0.000 description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 19
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 19
- 239000003921 oil Substances 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 16
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 16
- 239000008346 aqueous phase Substances 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 15
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 15
- GJAWHXHKYYXBSV-UHFFFAOYSA-N quinolinic acid Chemical class OC(=O)C1=CC=CN=C1C(O)=O GJAWHXHKYYXBSV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000003960 organic solvent Substances 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 13
- 125000000524 functional group Chemical group 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000012299 nitrogen atmosphere Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000010791 quenching Methods 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 125000004494 ethyl ester group Chemical group 0.000 description 10
- 150000003053 piperidines Chemical class 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 206010010904 Convulsion Diseases 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 229940043279 diisopropylamine Drugs 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000012467 final product Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- PTLWNCBCBZZBJI-UHNVWZDZSA-N (2s,3r)-piperidine-2,3-dicarboxylic acid Chemical class OC(=O)[C@@H]1CCCN[C@@H]1C(O)=O PTLWNCBCBZZBJI-UHNVWZDZSA-N 0.000 description 7
- MTJGVAJYTOXFJH-UHFFFAOYSA-N 3-aminonaphthalene-1,5-disulfonic acid Chemical compound C1=CC=C(S(O)(=O)=O)C2=CC(N)=CC(S(O)(=O)=O)=C21 MTJGVAJYTOXFJH-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 230000006378 damage Effects 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- RLJMLMKIBZAXJO-UHFFFAOYSA-N lead nitrate Chemical compound [O-][N+](=O)O[Pb]O[N+]([O-])=O RLJMLMKIBZAXJO-UHFFFAOYSA-N 0.000 description 7
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- LXRUAYBIUSUULX-ZJRLKYRESA-N (2r)-2-amino-3-methylbutanedioic acid Chemical compound OC(=O)C(C)[C@@H](N)C(O)=O LXRUAYBIUSUULX-ZJRLKYRESA-N 0.000 description 6
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 description 6
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960005261 aspartic acid Drugs 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- UAEWCWCMYQAIDR-UHFFFAOYSA-N diethyl methyl phosphate Chemical compound CCOP(=O)(OC)OCC UAEWCWCMYQAIDR-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 238000004255 ion exchange chromatography Methods 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- UDTYWUIFWZDIDT-VETVTEPKSA-N (3R)-3-[3-iodopropyl-[9-(4-methylphenyl)-9H-fluoren-1-yl]amino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC1=CC=C(C=C1)C2C3=CC=CC=C3C4=C2C(=CC=C4)N(CCCI)[C@H](CC(=O)O)C(=O)OCC5=CC=CC=C5 UDTYWUIFWZDIDT-VETVTEPKSA-N 0.000 description 5
- 108090000371 Esterases Proteins 0.000 description 5
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 5
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 5
- 235000014443 Pyrus communis Nutrition 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 230000007071 enzymatic hydrolysis Effects 0.000 description 5
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 5
- 150000007857 hydrazones Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 210000000653 nervous system Anatomy 0.000 description 5
- 150000002923 oximes Chemical class 0.000 description 5
- HXEACLLIILLPRG-PTQBSOBMSA-N piperidine-2-carboxylic acid Chemical class O[13C](=O)C1CCCCN1 HXEACLLIILLPRG-PTQBSOBMSA-N 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- RHPOFVFYZREVEF-UHFFFAOYSA-N 4-(dibenzylamino)butanoic acid Chemical compound C=1C=CC=CC=1CN(CCCC(=O)O)CC1=CC=CC=C1 RHPOFVFYZREVEF-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000002168 alkylating agent Substances 0.000 description 4
- 229940100198 alkylating agent Drugs 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- MVVHKGOKEBFZMT-UHFFFAOYSA-N 1-bromo-2-phenyl-9h-fluorene Chemical compound BrC1=C2CC3=CC=CC=C3C2=CC=C1C1=CC=CC=C1 MVVHKGOKEBFZMT-UHFFFAOYSA-N 0.000 description 3
- HAWVGXRATDEKIG-UHFFFAOYSA-N 3-(2-phosphonoethanimidoyl)piperidine-2-carboxylic acid Chemical class OC(=O)C1NCCCC1C(=N)CP(O)(O)=O HAWVGXRATDEKIG-UHFFFAOYSA-N 0.000 description 3
- HYQXNCDBSALQLB-UHFFFAOYSA-N 9-bromo-9-phenylfluorene Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1(Br)C1=CC=CC=C1 HYQXNCDBSALQLB-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 230000007850 degeneration Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- RLZFVPPGVAHZPE-UHFFFAOYSA-N ethyl 4-iodobutanoate Chemical compound CCOC(=O)CCCI RLZFVPPGVAHZPE-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000003257 excitatory amino acid Substances 0.000 description 3
- 230000002461 excitatory amino acid Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 230000001146 hypoxic effect Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
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- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- 238000003419 tautomerization reaction Methods 0.000 description 1
- UWPGVKLXIRBXEI-PVAVSMNWSA-N tert-butyl (2r,3s)-3-(2-diethoxyphosphorylacetyl)-1-(9-phenyl-9h-fluoren-1-yl)piperidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@H]1[C@@H](C(=O)CP(=O)(OCC)OCC)CCCN1C1=CC=CC2=C1C(C=1C=CC=CC=1)C1=CC=CC=C12 UWPGVKLXIRBXEI-PVAVSMNWSA-N 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- XJJBXZIKXFOMLP-UHFFFAOYSA-N tert-butyl pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1CCCN1 XJJBXZIKXFOMLP-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Claims (12)
1. Förfarande för framställning av heterocykliska NMDA-antagonister, diastereomerer och farmaceutiskt god-5 tagbara salter därav, M O N ® (I) ^C-CH2-P-(ORi)2 A 10 väri Rj representerar väte, en C1.4-alkyl- eller CF3-grupp, M är O, en N-0-R4-grupp eller en N-N-R4-grupp, där R4 H representerar väte eller en C1.4-alkyl- eller alkylfenyl-15 grupp, A representerar en av följande substituenter: d Re |Rs .-ft ti
20. N A , \ N X C0-0R2 V C0-0R2 1 :V· H H 25 « · • · .30 ΐ C0-0R2 R3 'CO-ORJ H h • · • · R2 representerar väte, en C^-alkyl-, cykloalkyl-, tri-alkylamino-, alkylfenyl-, fenyl-, substltuerad fenyl- el-35 ler trifluormetylgrupp, R3 representerar väte eller en C^- 97388 117 alkyl-, fenyl-, alkylfenyl- eller cyklohexylmetylgrupp, R5 representerar väte eller en linjär C^-alkyl- eller alkyl-fenylgrupp, och R6 representerar väte eller en C1.4-alkyl, fenyl-, alkylfenyl- eller cyklohexylmetylgrupp; 5 kännetecknat av att man a) för framställning av sädana föreningar med for-meln (I) där M är 0 kopplar en fosfonatester med formeln (5) O
2. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att M är O.
3. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att M är N-0-R4-H. 20
4. Förfarande enligt patentkrav 1, k ä n n e - H l tecknat av att M är N-N-R4.
5. C0-0R2 H
5. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att R3 är väte. 25
6. Förfarande enligt patentkrav 1, känne- :V tecknat av att A är jpr
30 R3S ^ C0-0R2 .·:· H ♦ ♦ ♦ ·
7. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att A är 35 119 97388 Rs Rb ""~\N
8. Förfarande enllgt patentkrav 1, k ä n n e -tecknat av att A är 10 R3 \ni y CO-OR2 H 15
9. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att A är R6 Rs 20 \--^ XX \ N x CO-OR2 H 25 10. Förfarande enligt patentkrav 8, k ä n n e - :V tecknat av att R5 och R3 är väteatomer.
10 CHalMORj'Ja (5) där R1' motsvarar den ovan definierade Rx, med en lämplig heterocyklisk grupp, som är ;
15 Rs \ fcz ti R3 X N A , \ N / C0-0R2 j CO-OR2 I
20. P "«'Ct eller
25. CO-OR2 I CO-OR2 P P « · där Z representerar en grupp -C(0)0-alk, där alk är en linjär Cj^-alkylgrupp, P är en lämplig skyddsgrupp eller H 30 och R2, R3, R5 och R6 är ovan definierade, eller φ · *··· (b) alternativt för framställning av sädana före- « · *♦* ningar med formeln (I) där M är 0 bringar den ovan defini- • · erade fosfonatestern med formeln (5) att reagera med ett N-skyddat piperidinkarboxylsyraanhydridderivat med formeln 35 (4) 97388 118 >Ό^ί 5 pg 0 där R3 är ovan definlerad och Pg en skyddsgrupp, eller (c) för framställning av sädana föreningar med for-meln (I) i vilka M är -N-0-R4 eller -N-NH-R4, kondenserar 10 en förening med formeln (I), där M är 0, med en förening med formeln MH2, där M är -N-0-R4 eller -N-NH-R4/ och (d) vid behov avlägsnar N-skyddsgrupperna frän den sä erhällna föreningen, isolerar föreningen i dess diaste-reomerer eller omvandlar den tili ett farmacetiskt godtag- 15 bart sait.
11. Förfarande enligt patentkrav 1, k ä n n e -tecknat av att man framställer en 3-(fosfono-acetyl)piperidin-2-karboxylsyra. # 30
12. Förfarande enligt patentkrav 1, k ä n n e - tecknat av att man framställer en 3(S)-(fosfono-’·] . acetyl)piperidin-2(R)-karboxylsyra. \ ·
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US52529090A | 1990-05-17 | 1990-05-17 | |
| US52529090 | 1990-05-17 | ||
| US67515691 | 1991-03-28 | ||
| US07/675,156 US5194430A (en) | 1990-05-17 | 1991-03-28 | Heterocyclic-nmda antagonists |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI912382A0 FI912382A0 (sv) | 1991-05-16 |
| FI912382A FI912382A (sv) | 1991-11-18 |
| FI97388B FI97388B (sv) | 1996-08-30 |
| FI97388C true FI97388C (sv) | 1996-12-10 |
Family
ID=27061745
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI912382A FI97388C (sv) | 1990-05-17 | 1991-05-16 | Förfarande för framställning av heterocykliska NMDA-antagonister |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US5194430A (sv) |
| EP (1) | EP0457324B1 (sv) |
| JP (1) | JP2977950B2 (sv) |
| KR (1) | KR100196239B1 (sv) |
| CN (1) | CN1027695C (sv) |
| AT (1) | ATE131172T1 (sv) |
| AU (1) | AU641657B2 (sv) |
| CA (1) | CA2042473C (sv) |
| DE (1) | DE69115116T2 (sv) |
| DK (1) | DK0457324T3 (sv) |
| ES (1) | ES2083478T3 (sv) |
| FI (1) | FI97388C (sv) |
| GR (1) | GR3019047T3 (sv) |
| HU (1) | HU208831B (sv) |
| IE (1) | IE70437B1 (sv) |
| IL (1) | IL98148A (sv) |
| NO (1) | NO300502B1 (sv) |
| NZ (1) | NZ238124A (sv) |
| PT (1) | PT97692B (sv) |
| TW (1) | TW308596B (sv) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260286A (en) * | 1992-10-16 | 1993-11-09 | Japan Tobacco, Inc. | 2-piperidinecarboxylic acid derivatives useful as NMDA receptor antagonists |
| WO2002072542A2 (en) * | 2001-03-08 | 2002-09-19 | Emory University | Ph-dependent nmda receptor antagonists |
| BRPI0813001A2 (pt) | 2007-06-29 | 2019-09-24 | Univ Emory | composto, método de tratamento ou profilaxia de dor neuropática e composição farmacêutica |
| CN102952065A (zh) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | 一种拆分顺式2,3-吡啶二甲酸酯的方法 |
| CN102952130B (zh) * | 2011-08-24 | 2016-03-23 | 重庆华邦胜凯制药有限公司 | 手性合成(s,s)-2,8-二氮杂双环壬烷的方法 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2706194A (en) * | 1951-05-14 | 1955-04-12 | Shell Dev | Esters of phosphonic acids |
| NL299936A (sv) * | 1963-10-30 | 1965-08-25 | ||
| JPS5251028A (en) * | 1975-10-22 | 1977-04-23 | Nippon Tokushu Noyaku Seizo Kk | Herbicide |
| US4094974A (en) * | 1977-02-24 | 1978-06-13 | Stauffer Chemical Company | Isoxazole phosphates and phosphonates |
| US4139708A (en) * | 1977-05-24 | 1979-02-13 | Sk&F Lab Co. | Intermediates and processes useful for preparing medicinal agents imidazolemethylphosphonium salts |
| CA1248531A (en) * | 1984-04-17 | 1989-01-10 | Jeffrey C. Watkins | 4-substituted piperazine-2-carboxylic acids |
| PH23848A (en) * | 1985-05-24 | 1989-11-23 | Ciba Geigy Ag | Certain phosphonic acids and derivatives |
| US4906621A (en) * | 1985-05-24 | 1990-03-06 | Ciba-Geigy Corporation | Certain 2-carboxypiperidyl-alkylene phosphonic acids and esters thereof useful for the treatment of disorders responsive to N-methyl-D-aspartate receptor blockade |
| US4746653A (en) * | 1986-02-28 | 1988-05-24 | Ciba-Geigy Corporation | Certain hetero phosphonic acid derivatives of 2-piperidine or 2-tetrahydropyridinecarboxylates and esters thereof which are useful for the treatment of disorders responsive to blockade of the NMDA receptor in mammals |
| US4657899A (en) * | 1986-04-09 | 1987-04-14 | Nova Pharmaceutical Corporation | Antagonists of specific excitatory amino acid neurotransmitter receptors |
| IL84492A0 (en) * | 1986-11-21 | 1988-04-29 | Ciba Geigy Ag | Unsaturated phosphonic acids and derivatives |
| SE9003652D0 (sv) * | 1990-11-15 | 1990-11-15 | Astra Ab | New heterocyclic compounds |
-
1991
- 1991-03-28 US US07/675,156 patent/US5194430A/en not_active Expired - Fee Related
- 1991-05-13 NZ NZ238124A patent/NZ238124A/xx unknown
- 1991-05-13 CA CA002042473A patent/CA2042473C/en not_active Expired - Fee Related
- 1991-05-14 AU AU76498/91A patent/AU641657B2/en not_active Ceased
- 1991-05-14 TW TW080103761A patent/TW308596B/zh active
- 1991-05-15 IL IL9814891A patent/IL98148A/en active IP Right Grant
- 1991-05-16 FI FI912382A patent/FI97388C/sv not_active IP Right Cessation
- 1991-05-16 PT PT97692A patent/PT97692B/pt not_active IP Right Cessation
- 1991-05-16 ES ES91107955T patent/ES2083478T3/es not_active Expired - Lifetime
- 1991-05-16 NO NO911916A patent/NO300502B1/no not_active IP Right Cessation
- 1991-05-16 EP EP91107955A patent/EP0457324B1/en not_active Expired - Lifetime
- 1991-05-16 CN CN91103185A patent/CN1027695C/zh not_active Expired - Fee Related
- 1991-05-16 HU HU911649A patent/HU208831B/hu not_active IP Right Cessation
- 1991-05-16 IE IE167691A patent/IE70437B1/en unknown
- 1991-05-16 DK DK91107955.6T patent/DK0457324T3/da active
- 1991-05-16 AT AT91107955T patent/ATE131172T1/de not_active IP Right Cessation
- 1991-05-16 DE DE69115116T patent/DE69115116T2/de not_active Expired - Fee Related
- 1991-05-17 JP JP3140636A patent/JP2977950B2/ja not_active Expired - Fee Related
- 1991-05-17 KR KR1019910008036A patent/KR100196239B1/ko not_active IP Right Cessation
-
1993
- 1993-11-30 US US08/159,913 patent/US5470844A/en not_active Expired - Lifetime
-
1996
- 1996-02-21 GR GR960400451T patent/GR3019047T3/el unknown
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| BB | Publication of examined application | ||
| MA | Patent expired |